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Blood-Borne Cancer Metastasis: From Mechanisms To Therapeutics

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Li, Jiahe

Abstract

Metastasis is the cause of about 90% of cancer-associated deaths, yet the mechanisms governing this clinically important process remain poorly understood. Distant metastases rely on hematogenous dissemination of circulating tumor cells (CTCs). Many studies have shown that CTCs do not mobilize in the circulation alone. Instead, through heterotypic interactions with endothelial cells and different types of blood cells, CTCs acquire the potential to metastasize to distant organs. For successful establishment of metastases, CTCs must adhere and transmigrate through the endothelium layer. Using prostate cancer (PCa) as a model, we discovered and investigated the role of [alpha]-1, 3-fucosyltransferase 6 (FT6) gene in PCa bone metastasis. It was found that overexpression of FT6 mediated enhanced adhesion of cancer cells to bone marrow endothelium and subsequent bone metastasis via expression of unique glycan structure on CTCs. This study can potentially lead to effective treatment of bone metastasis in PCa by targeting the FT gene. Moreover, the novel PCa bone metastasis mouse model can provide a platform for screening and identifying new chemical inhibitors to prevent bone metastasis. The second part of this thesis focuses on development of effective therapeutic strategies for CTC targeting. TNF-related apoptosis-inducing ligand (TRAIL) was chosen as it has been suggested as a potent cytokine in killing CTCs. TRAIL resistance, however, is commonly detected in certain cancer subpopulations. A novel chemical compound, Piperlongumine was found to be capable of sensitizing TRAILresistant cancer cells to apoptosis through generation of reactive oxygen species (ROS). In addition to the drug combination approach, two unique drug delivery platforms specific for CTC targeting were also developed. A large body of experimental evidence makes the case that platelets are physically associated with CTCs to facilitate metastasis in many cancer diseases. Inspired by this phenomenon, we first took a biomaterial approach to functionalize silica particles with platelet membranes and TRAIL. We also genetically modified bone marrow stem cells to produce TRAILexpressing platelets. Both methods have demonstrated effective reduction of metastases in experimental mouse cancer models.